The primary pharmacologic treatment for depression over the past several decades has been drugs that inhibit synaptic reuptake of monoamine neurotransmitters. Although the importance of monoamine neurotransmission in antidepressant efficacy cannot be discounted, recent evidence indicates other neurotransmitter systems may play a role in the mechanism of action of antidepressants. Furthermore, the limitations of current antidepressant treatments necessitate the development of novel compounds to treat depression. A growing body of evidence suggests that cholinergic systems may be potential targets for the development of novel antidepressant compounds. Stimulation of cholinergic systems with agents such as the cholinesterase inhibitor physostigmine, can induce depression-like symptoms in individuals with affective disorders, as well as in normal subjects. Studies at the cellular, physiological and behavioral levels have shown that a wide range of antidepressants, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and atypical antidepressants, all act as non-competitive antagonists of nicotinic acetylcholine receptors. We hypothesize that antagonism of high affinity neuronal nAChRs is an important component of the therapeutic mechanism of action of a classical antidepressant compound, and further, that nicotinic receptor antagonists may be novel therapeutic agents that could be useful in patients who are not responsive to current pharmacological treatments. We propose to test this hypothesis and to investigate the molecular mechanisms underlying the antidepressant-like effect of nicotinic antagonists by identifying the nicotinic receptor subtypes critical for the antidepressant-like effects of nicotinic antagonists using knockout mouse models, by determining whether acute and chronic administration of nicotinic partial agonists results in antidepressant-like actions in rodent models of depression-like behavior, by investigating the neurotransmitter systems critical for the antidepressant-like effects of nicotinic antagonists and by determining whether nicotinic antagonists can stimulate plasticity in the hippocampal formation similarly to classical antidepressants. These studies should be an important step in identifying novel nicotinic agents that could have efficacy as antidepressants.